Chronic Critical Illness and the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome

Abstract

Dysregulated host immune responses to infection often occur, leading to sepsis, multiple organ failure, and death. Some patients rapidly recover from sepsis, but many develop chronic critical illness (CCI), a debilitating condition that impacts functional outcomes and long-term survival. The "Persistent Inflammation, Immunosuppression, and Catabolism Syndrome" (PICS) has been postulated as the underlying pathophysiology of CCI. We propose that PICS is initiated by an early genomic and cytokine storm in response to microbial invasion during the early phase of sepsis. However, once source control, antimicrobial coverage, and supportive therapies have been initiated, we propose that the persistent inflammation in patients developing CCI is a result of ongoing endogenous alarmin release from damaged organs and loss of muscle mass. This ongoing alarmin and danger-associated molecular pattern signaling causes chronic inflammation and a shift in bone marrow stem cell production toward myeloid cells, contributing to chronic anemia and lymphopenia. We propose that therapeutic interventions must target the chronic organ injury and lean tissue wasting that contribute to the release of endogenous alarmins and the expansion and deposition of myeloid progenitors that are responsible for the propagation and persistence of CCI.

Keywords: PICS; critical illness; immunosuppression; inflammation; sepsis.

Figure 1

Proposed hypothesis for the PICS. Abbreviations: SIRS, systemic inflammatory response syndrome; MDSC, myeloid-derived suppressor cell; sPDL-1, soluble programmed death ligand-1; LTAC, long-term acute care facility; PICS, persistent inflammation, immunosuppression, and catabolism syndrome.

Figure 2

Proposed self-perpetuating cycle of persistent inflammation driving organ injury through a failure of metabolic adaptation, leading to release of endogenous alarmins and bone marrow changes. Three cycles drive CCI: muscle wasting (discussed in Section “Skeletal Muscle as a Target for Oxidant Injury and DAMP Release”), organ injury (discussed in Section “Role of AKI in CCI”), and emergency myelopoiesis (discussed in Section “Abnormal Myelopoiesis and MDSCs”).

Figure 3

Survival of CCI (n = 71) or RAP (n = 66) patients 6 months after sepsis. Trajectories were classified as early death (blue), RAP (green), and CCI (red). Kaplan–Meier analysis demonstrated significant differences (p < 0.01) in survival between groups. Abbreviations: CCI, chronic critical illness; RAP, rapid recovery.

Figure 4

Biomarker concentrations in patients with CCI and RAP. Blood samples were collected at 0.5, 1, 4, 7, 14, 21, and 28 days after sepsis onset. Differences in concentrations between CCI (filled circles) and RAP (filled triangles) cohorts at individual time points are identified with an asterisk at a p value less than 0.05 using nonparametric tests. Patients with CCI had evidence of prolonged immunosuppression. Abbreviations: CCI, chronic critical illness; RAP rapid recovery; IL-10, interleukin-10; sPDL-1, soluble programmed death ligand-1.